Pitx2c inhibition increases atrial fibroblast activity: Implications in atrial arrhythmogenesis

European Journal of Clinical Investigation
Yu-Hsun KaoYi-Jen Chen

Abstract

A Pitx2c deficiency increases the risk of atrial fibrillation (AF). Atrial structural remodelling with fibrosis blocks electrical conduction and leads to arrhythmogenesis. A Pitx2c deficiency enhances profibrotic transforming growth factor (TGF)-β expression and calcium dysregulation, suggesting that Pitx2c may play a role in atrial fibrosis. The purposes of this study were to evaluate whether a Pitx2c deficiency modulates cardiac fibroblast activity and study the underlying mechanisms. A migration assay, proliferation analysis, Western blot analysis and calcium fluorescence imaging were conducted in Pitx2c-knockdown human atrial fibroblasts (HAFs) using short hairpin (sh)RNA or small interfering (si)RNA. Compared to control HAFs, Pitx2c-knockdown HAFs had a greater migration but a similar proliferative ability. Pitx2c-knockdown HAFs had a higher calcium influx with enhanced phosphorylation of calmodulin kinase II (CaMKII), α-smooth muscle actin and matrix metalloproteinase-2. In the presence of a CaMKII inhibitor (KN-93, 0.5 μmol/L), control and Pitx2c-knockdown HAFs exhibited similar migratory abilities. These findings suggest that downregulation of Pitx2c may regulate atrial fibrosis through modulating calcium homeostasis, w...Continue Reading

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Citations

Nov 21, 2020·JACC. Clinical Electrophysiology·Stanley Nattel, Martin Aguilar
May 19, 2021·Pflügers Archiv : European journal of physiology·Wenli DaiChristopher R Weber

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